The overall objective of this grant is to use genetics to define mechanisms underlying immunopathogenesis of insulin dependent diabetes mellitus (Type 1 Diabetes, T1D) in the NOD mouse. Our objective in this final renewal of the grant is to delineate the natural mechanisms whereby autoreactive T cells may be downregulated and understand why these mechanisms fail in the NOD mouse. Studies using gene targeted NOD stocks are proposed to investigate whether ADP-ribosyltransferases, enzymes expressed on the surface of NOD CD4+ and CD8+ T cells, play a role in down-regulating autoimmune T-effectors. Studies are also outlined which take advantage of the availability of stocks of NOD mice with genetically engineered mutations in specific cell surface homing molecules (integrins). Combinations of these integrins (L-selectin and Beta7) are necessary for normal colonization of the gut associated lymphoid tissue (GALT). The Beta7 integrin is required for T-effector cells to home to the pancreas and mediate autoimmune destruction of the pancreatic beta cells. These unique stocks will permit analysis of the interaction between the gut associated lymphoid tissue and diabetogenic catalysts in natural ingredient diet required to activate these diabetogenic T-effectors. Experiments are proposed to elucidate the mechanism of diabetes suppression in NOD mice by oral insulin administration. These latter investigations are of particular importance in view of an ongoing NIDDK trial to prevent T1D in humans deemed at high risk by oral insulin treatment.